Genetic aberrations that render cells incapable of executing DNA damage-induced apoptosis, such as loss of p53 or overexpression of Bcl-2, contribute to the de novo or acquired resistance of B-cell malignancies to genotoxic anticancer agents. The overall objective of this proposal is to identify therapeutic strategies against B-cell malignancies that are based on modulation of the molecular determinants of B cell survival. Tumor cell death may be triggered by antibody-mediated engagement of specific B-cell molecules [B-cell receptor/surface immunoglobulin (BCR/sIg) or CD20] or ligation of specific death receptors (TRAIL-R1/R2) with TRAIL/Apo2L (tumor necrosis factor- related apoptosis-inducing ligand). Since death receptors and DNA damage induce independent signaling pathways that converge at the level of the mitochondria to form the apoptosome, death- receptor-transduced signals may offer a potential mechanism of eliminating p53-deficient or Bcl-2-overexpressing B-cell tumors. However, death receptor-induced signals may be counteracted by nuclear factor-kappa B (NF-kB), a family of transcription factors that is activated by costimulatory interactions, viral proteins, or genetic aberrations in B-cell tumors. The central hypothesis to be tested is that B-cell tumors can be eliminated via ligand/antibody-mediated activation of death receptors in combination with agents that inhibit NF-kB. The specific aims are: 1. Define the molecular mechanisms and determinants of anti-Ig, anti-CD20-, or TRAIL/Apo2L-mediated apoptosis of Bcl-2- overexpressing or p53-deficient B cells or B-cell tumors. 2. Define the role of NF-kB in protection of B-cell tumors from death receptor-induced apoptosis: a. Identify the molecular mechanism(s) by which costimulatory signals (CD40/CD40L and TACI/BLyS) activate NF-kB and define the role of specific NF-kB-dependent proteins in protection of B cell tumors from death receptor-induced apoptosis. b. Investigate whether inhibition of NF-kB with agents that target the Ikappa B kinase (IKK) complex can augment anti-Ig-, anti-CD20-, or TRAIL/Apo2L-induced apoptosis of B-cell malignancies. The proposed studies could provide a foundation for the design of potentially synergistic combinatorial regimens of death receptor- binding antibodies/ligands and NF-kB inhibitors for treatment of B-cell malignancies that resist conventional chemotherapy or irradiation.